BRPI0614752A2 - process for preparing a compound, compound, radiopharmaceutical kit, and cartridge for a radiopharmaceutical kit - Google Patents

Abstract

PROCESS FOR PREPARING A COMPOUND, COMPOUND, RADIO-PHARMACEUTICAL KIT, AND CARTRIDGE FOR A RADIO-PHARMACEUTICAL KIT. The invention relates to a process for the preparation of a compound of formula (I): R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl; comprising: (i) reaction with fluoride, suitably fluoride [18F], of a corresponding compound of formula (II): wherein R2 is selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C6-14aryl, C6- Arylalkyl, - (CH 2 CH 2 O) q -CH 3 wherein q is an integer from 1 to 10; R1 is as defined for the compound of formula (I); and R3 is a leaving group. Certain new precursors of formula (II) and radiopharmaceutical kits containing such precursors are also claimed.

Description

"PROCESS FOR PREPARING A COMPOUND, COMPOUND, RADIOPHARMACEUTICAL KIT, AND CARTRIDGE FOR AN ARMACETIC RADIOF KIT"

The present invention relates to novel fluorination processes, particularly fluorination [18F] of certain aromatic compounds, and novel precursors used in the process. The invention has particular utility for a class of benzothiazole derivatives which are known as in vivo imaging agents.

Fluorination of aromatic compounds can be performed via molecular fluorine electrophilic reaction, however, electrophilic fluorination of fluorine aromatic compounds is generally an unsatisfactory and non-selective method. Different electrophilic fluorination reagents from molecular fluorine have been developed, such as CH3COOF "AcOF" but suffer from several disadvantages. For radiofluorination [18F], the difficult conditions, and the unsatisfactory availability of electrophilic [18F] fluorination methods, and the low specific activity of the products obtained mean that it is not a favorable approach for commercial production of [18F] labeled products. Nucleophilic fluorination methods using fluoride are most commonly used. Fluoride [I8F] is a more widely available reagent than electrophilic reagents and the products obtained are of higher specific activity which is advantageous in the in vivo imaging field. Nucleophilic fluorination of aromatic rings, particularly those that are rich in electrons can be problematic. For example, nucleophilic fluorination of anilines, where the amino group contributes to the electron density of the aromatic ring is difficult to perform. The present invention provides a suitable precursor for nucleophilic fluorination to give a fluorinated aniline, which combines numerous beneficial effects including enhanced activation of the aromatic ring for fluorination, few steric effects on the fluorination reaction, and easy conversion to the fluorinated aniline product. According to the invention there is provided a process for preparing a compound of formula (1):

<formula> formula see original document page 3 </formula>

wherein phenyl ring A is optionally substituted with 1 to 4 substituents; R 1 is selected from C 1-6 alkyl, C 2-6 ^ 1 alkenyl, and C 2-6 alkynyl; which comprises:

(i) reaction of a corresponding compound of formula (II):

<formula> formula see original document page 3 </formula>

wherein ring A is optionally substituted as defined

for the compound of formula (I); .2

R is selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C6aryl, C6arylalkyl, - (CH2 CH2O) q-CH3 wherein q is an integer from 1 to 10;

R1 is as defined for the compound of formula (I); and

.3 '

R is an leaving group;

with fluoride to give a compound of formula (III)

<formula> formula see original document page 3 </formula>

.12 · wherein ReR are as defined for the compound of

formula (I) and phenyl ring A is substituted as defined for the compound of

formula (I); followed by step (ii) and optionally step (iii) in any

* · 2

(ii) conversion of -C (O) R group to hydrogen, suitably by

hydrolysis (iii) removal of any other protecting groups.

Phenyl ring A is optionally substituted with 1 to 4 organic substituents for example selected from fluoro, chloro, bromo, iodo, cyano, nitro, -R, -OR, -OC (O) R, -C (O) R, -SR , -NR2, -C (O) NR2 wherein R at each occurrence is selected from C1-6alkyl, C2-6alkenyl, C2-6alkyl, C1-6alkoxy-C1-6alkyl, C2-6halo-alkyl, C2.6halo-alkenyl , C2. 6halo-alkynyl, C1-6 halo-C1-6 alkoxyalkyl, C5-12aryl, C5-12 hetaryl in which said aryl and hetaryl substituents may be further substituted with the non-aryl and non-hetaryl substituents listed for phenyl ring A, and a protected derivative of any of them.

R2 in the compound of formula (II) is selected from hydrogen, C1-10 alkyl (more suitably C1-6 alkyl, even more suitably methyl), C1-10haloalkyl (more suitably C1-6haloalkyl such as C1-6fluoroalkyl, for example trifluoromethyl), C 6-14 aryl (suitably phenyl), C 6-14 arylalkyl (suitably phenyl-C 1-4 alkyl, for example benzyl), and - (CH 2 CH 2 O) q -CH 3 where q is an integer from 1 to 10 Compounds of formula (II) wherein R 2 is C 4-10 alkyl or - (CH 2 CH 2 O) q -CH 3 wherein q is an integer from 1 to 10 may be used in the process where it is desirable to increase the solubility of the compound of formula ( II) and as such these compounds and the process according to the invention using them form separate aspects of the invention. Preferably, R2 in the compound of formula (II) is selected from hydrogen and C1-4 alkyl, more preferably R2 is hydrogen.

R3 in the compound of formula (II) is a leaving group capable of being substituted by fluoride and is suitably selected from:

nitro,

-N2 +,

chlorine, bromine, iodine,

-NR4 (C1-4 alkyl) S +

wherein R4 is C1-4 alkyl or a group of formula (X): <formula> formula see original document page 5 </formula>

Wherein R5 is selected from C1-4 alkyl, C1-4 haloalkyl such as C1-6 perfluoro-alkyl, aryl such as phenyl or tolyl (e.g. para-tolyl), and a group of formula (X) as defined. above; and

<formula> formula see original document page 5 </formula>

wherein R 6 is selected from hydrogen, C 1-6 alkyl, halo, nitro, and a group of formula (X) as defined above.

R3 in the compound of formula (II) is suitably selected from:

nitro,

-N2 +,

chlorine,

bromine,

iodine,

-NR4 (C 1-6 alkyl) 2+ wherein R 4 is C 1-6 alkyl

-OSO2R5 wherein R5 is selected from C1-6alkyl, C1-6haloalkyl such as C1-6perfluoroalkyl, aryl such as phenyl or tolyl (e.g. para-tolyl); and

<formula> formula see original document page 5 </formula>

wherein R6 is selected from hydrogen, C1-6alkyl, halo, and nitro.

In a particular aspect of the invention, R 3 is nitro.

In the process according to the invention, the use of compounds of formula (II) wherein R3 comprises a group of formula (X) allows fluorination to be performed in solid phase which may simplify purification of the fluorinated product because any unreacted precursor remains. bound to the solid support and may be removed from the solution phase product by filtration.

In the group of formula (X), the Solid Support may be any solid solid phase support that is insoluble in any solvents to be used in the process but to which the Binder and / or compound of formula (II) may be covalently bonded. Examples of Suitable Solid Support include polymers such as polystyrene (which may be block grafted, for example with poly (ethylene glycol), polyacrylamide, or polypropylene or glass or silicon coated with such a polymer. The Solid Support may be in the form of discrete small particles such as globules or pins, or as a coating on the inner surface of a cartridge or a microfabricated vessel.

In the group of formula (X), the Binder may be any suitable organic group which serves to sufficiently spac the reactive site of the solid support structure to maximize reactivity. Suitably, the Linker comprises zero to four aryl (suitably phenyl) and / or one C1-6 alkyl or C1-4 haloalkyl (suitably C1-6 fluoroalkyl) groups, and optionally one to four additional functional groups such as amide or sulfonamide groups. Examples of such a binder are well known to those skilled in the art of solid phase chemistry, but include: <formula> formula see original document page 7 </formula>

where in each occurrence, η is an integer from 0 to 3 and RL is hydrogen or C1-6alkyl.

Step (i) of the process according to the invention ie reaction of a compound of formula (II) with fluoride, suitably fluoride [F] may be carried out using a fluoride source such as NaF, KF, CsF, tetraalkyl ammonium fluoride , or tetraalkyl phosphonium fluoride, suitably a source of fluoride [18F] such as Na18F, K18F, Cs18F, tetraalkylammonium fluoride [18F] (e.g. tetrabutylammonium fluoride [18F]), or tetraalkylphosphonium fluoride F of tetraalkyl phosphonium. To enhance reactivity to fluoride, a phase transfer catalyst such as an amino polyether or crown ether, for example 4,7,13,16,21,24 hexaoxa-1,10-diaza-bicyclo [8, 8.8] hexacosane (Kryptofix 2.2.2) may be added and the reaction carried out in a suitable solvent. These conditions give reactive fluoride ions. Optionally, a free radical deactivator may be used to improve fluorination yields as described in WO2005 / 061415. The term "free radical deactivator" is defined as any agent that interacts with free radicals and inactivates them. A suitable free radical deactivator for this purpose may be selected from 2,2,6,6-Tetramethylpiperidine-N-Oxide (TEMPO), 1,2-diphenylethylene (DPE), ascorbate, para-amino acid. benzoic acid (ΡABA), α-tocopherol, hydroquinone, di-t-butyl phenol, β-carotene and gentitic acid. Preferred free radical deactivators for use in the process of the invention are TIME and DPE, with TIME being more preferred.

Treatment with fluoride, suitably fluoride [, 8F] in step (i) may be carried out in the presence of a suitable organic solvent such as acetonitrile, dimethylformamide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, sulfolane, N-methylpyrrolidininone, or in an ionic liquid such as an imidazole derivative (e.g. 1-ethyl-3-methylimidazole hexafluoro phosphate), a pyridinium derivative (e.g. (1-butyl-4-methylpyridinium tetrafluoro borate), a phosphonium compound, or tetraalkyl ammonium compound at a non-extreme temperature, e.g. 15 ° C to 180 ° C, preferably at elevated temperature , such as 80 ° C to 150 ° C, for example around 120 ° C. The organic solvent is suitably anhydrous, but in some cases may contain low water levels.

In one aspect of the invention, the fluoro group in the compound of formula (1) is fluoro [18F] and the fluoride used in process step (i) is fluoride [F]. There is a particular need for new radiofluorination methods, especially for radiofluorination of electron rich aromatic systems.

Step (li) in the process, ie conversion of -C (O) R group to hydrogen, is suitably effected by acidic or basic hydrolysis using an organic or inorganic acid at non-extreme temperature, for example room temperature to reflux temperature. . The reaction may be carried out in the presence of an aqueous solvent or organic solvent, for example C1-4 alcohol such as methanol or ethanol or acetonitrile, or a mixture of aqueous and organic solvents.

Suitable acids in step (ii) include hydrobromic, trifluoroacetic, phosphoric, and hydrochloric.

Suitable bases used in step (ii) include sodium hydroxide or potassium hydroxide. Use of sodium hydroxide in an organic solvent such as acetonitrile, at elevated temperatures for example around 100 ° C, may cause good radiochemical yields and facilitate purification of the fluorinated product.

Alternative bases used in step (ii) include non-nucleophilic bases such as sodium hydride. This method causes good radiochemical yields and also facilitates purification of the fluorinated product. Sodium hydride treatment may be carried out in a suitable aprotic solvent such as acetonitrile or propionitrile and at elevated temperature such as 40 ° C to 120 ° C, typically around 100 ° C. Sodium borohydride, lithium borohydride and lithium aluminum hydride are also suitable bases for use in step (ii).

As will be apparent to the person skilled in the art, sometimes the use of protective group strategies is necessary to prevent unwanted side reactions during organic synthesis. Examples of such strategies can be found in "Protecting Groups in Organic Synthesis", Theodora W. Greene and Peter G. M. Wuts, published by John Wiley & Sons Inc., which describes methods for incorporating and removing protecting groups. To avoid unnecessary steps, it is particularly beneficial if any remaining protecting groups in the compound of formula (III) are removed under the conditions of step (ii) in order to avoid a separate deprotection step.

As used herein, the term "alkyl" used alone or as part of another group means a straight chain or branched saturated hydrocarbon radical, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, or n-hexyl.

As used herein, the term "alkenyl" used alone or as part of another group means a straight or branched chain unsaturated hydrocarbon radical comprising at least one carbon-carbon double bond, such as ethenyl, propenyl, iso-propenyl, butenyl, isobutenyl, tert-butenyl, n-pentenyl, and n-hexenyl.

As used herein, the term "alchemy" used alone or as part of another group means a straight or branched chain unsaturated hydrocarbon radical comprising at least one carbon-carbon triple bond such as ethinyl, propynyl, iso-propynyl, butynyl, isobutynyl, tert-butynyl, n-pentinyl, and n-hexinyl.

As used herein, the term "halo" used alone or as part of another group means fluoro, chloro, bromo, or iodo.

As used herein, the term "aryl" used alone or as part of another group means a single aromatic hydrocarbon ring or a fused ring system such as phenyl or naphthyl.

As used herein, the term "hetaryl" used alone or as part of another group means a single aromatic hydrocarbon ring or a fused ring system that additionally comprises 1 or more heteroatoms selected from sulfur, nitrogen, and oxygen, such as pyridyl, thio -phenyl, benzothiazolyl, benzoxazolyl, or furyl.

The process according to the invention has particular utility for the synthesis of compounds of formula (I) wherein R1 is C1-6 alkyl, and particularly methyl, thus the processes wherein R1 in compounds of formula (I), (II), (III). C 1 -C 6 alkyl, and particularly methyl form a separate aspect of the invention.

The process according to the invention is particularly useful when the fluoro group in the compound of formula (I) is ortho or to the group - N (R1) C (O) R2 wherein -N (R1) C (O) R2 positioned ortho or to R 3 in the corresponding compound of formula (II) may activate R for nucleophilic fluoride substitution. Preferably, the fluoro group in the compound of formula (I) is ortho to the group -N (R1) C (O) R2 and the group R3 in the corresponding

1

The compound of formula (II) is ortho to the group -N (R) C (O) R.

Certain compounds of formula (I) are known to be used in diagnostic and therapeutic methods, for example the benzothiazole derivatives described for in vivo imaging of amyloid according to the methods described in WO 02/16333 and WO2004 / 083195. The previously described methods for preparing these benzothiazole derivatives, although suitable for preparing small amounts of the compounds, suffer from poor radiochemical yields and unsatisfactory reproducibility such that there is a need for improved processes for their preparation, particularly for a commercial environment. As mentioned above, nucleophilic fluorination of an aromatic ring can be problematic where the ring is rich in electrons. In the compounds of formula (Ia) and (Ib) below, the substitution pattern makes the aromatic ring difficult to fluorine. Attempts to design a stable precursor for fluorination which could then be readily converted into an end product were problematic as shown below in Example 3. Thus, in another aspect, a process for preparing a compound of formula ( Ia):

<formula> formula see original document page 11 </formula>

(La) R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

R7, R8, R9, and R10

are each independently selected from hydrogen, fluoro, chloro, bromo, iodo, C1-4 alkyl, C2-6 alkenyl, C2-4 alkynyl, (CH2) mORu (where m = 1.2, or 3), CF3, CH2-CH2Y5 O- CH 2 -CH 2 Y, CH 2 -CH 2 -CH 2 Y, O-CH 2 -CH 2 -CH 2 Y (wherein Y is selected from fluoro, chloro, bromo, and iodo), CN, (C = O) -R 11, N (Ru) 2, NO2, (C = O) N (R11) 2, (CO) R11, OR11, SR11, COOR11, Rph, CR11 = CRu-Rph, CR112-CR112-Rph (where Rph is a substituted or unsubstituted phenyl group). substituted with phenyl substituents being selected from any of the non-phenyl substituents defined for R 7 to R 10 and wherein R 11 is H or C 1-6 alkyl) and a protected derivative of either; and phenyl ring A is substituted with 1 to 3 substituents being selected from any of the non-phenyl substituents defined for R 7 to R 10;

which comprises:

(i) reaction of a corresponding compound of formula (IIa):

(IIa)

<formula> formula see original document page 12 </formula>

in which

R1 is defined for the compound of formula (Ia),

phenyl ring A is substituted as defined for the compound of formula (Ia); and

R2 is selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C6-14aryl, C6-4arylalkyl, - (CH2CH2O) q-CH3 wherein q is an integer from 1 to 10;

R3 is a leaving group as defined for the compound of formula (II);

R 7, R 8, R 9, and R 10 are as defined for the compound of formula (Ia);

with fluoride to give a compound of formula (IIIa)

<formula> formula see original document page 12 </formula>

wherein ReR are as defined for the compound of formula (11a), phenyl ring A is substituted as defined for the compound of formula (Ia);

R, R, and Rw are as defined for the compound of formula (la); followed by step (ii) and optionally step (iii) in any order:

(ii) conversion of -C (O) R group to hydrogen,

properly by hydrolysis

(iii) removal of any other protecting groups. In the compounds of formula (Ia), (Ha), and (IIIa) and the corresponding process according to the invention,

R7, R8, R9i and R10 are

suitably selected from hydrogen, hydroxyl, -NO2, -CN, -COOR11, -OCH2OR11 (where Rn is selected from hydrogen and C1-4 alkyl), Q.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkoxy, halo, and a protected derivative

m

of any of them. Suitable substituent derivatives of R substituents,

R8, R9, and R10

will be apparent to the person skilled in the art, and are described in Theodora W. Greene and Peter G. M. Wuts as noted hereinabove. Por7 8 9 10

For example, when R, R, R, or R is hydroxyl, the hydroxyl function is suitably protected as a C1-6 alkoxymethoxy group such as ethoxymethoxy or methoxy methoxy.

A preferred class of compounds of formula (Ia) for use in in vivo imaging of amyloid are those of formula (Ib).

<formula> formula see original document page 13 </formula>

wherein R1 is selected from C1-4 alkyl, C2-4 alkenyl, and C2-6 alkynyl; and

R 9 is selected from hydroxyl, -NO 2, -CN, -COOR 11, -OCH 2 OR 11 (wherein R 11 is selected from hydrogen and C 1-6 alkyl), C 1-4 alkyl, C 2-4 alkenyl, C 2-6 alkynyl, C 1-4 alkoxy, halo, and a derivative. is protected from any of them, and is preferably selected from hydroxyl, C 1-6 alkoxy, and a protected derivative of any one of them, and is more preferably selected from hydroxyl, methoxy, and a protected derivative of either. Therefore, according to one aspect of the invention there is provided a process for preparing a compound of formula (Ib):

<formula> formula see original document page 14 </formula>

in which

R1 is selected from C1-6 alkyls C2-6alkenyl, and C2-6alkynyl;

R 9 is selected from hydroxyl, -NO 2, -CN, -COOR, -OCH 2 OR, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halo, and a protected derivative of either, and is preferably selected from hydroxyl, C 1-6 alkoxy and a protected derivative of any one of them, and is more preferably selected from hydroxyl, methoxyl, and a protected derivative of either;

which comprises:

(i) reaction of a corresponding compound of formula (IIb):

<formula> formula see original document page 14 </formula>

wherein R1 is selected from C1-6alkyls C2-6alkenyl5 and C2-6alkynyl, and R is selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C6-14aryl, C6-14arylalkyl, - (CH2CH2O) q- CH3 where q is an integer from 1 to 10;

R3b is a leaving group as defined for the compound of formula (II);

R 9 is as defined for the compound of formula (Ib); with fluoride to give a compound of formula (IIIb) <formula> formula see original document page 15 </formula>

wherein ReR are as defined for the compound of formula (IIb);

R 9 is as defined for the compound of formula (Ib); followed by step (ii) and optionally step (iii) in any order

(ii) conversion of -C (O) R2 group to hydrogen, suitably by hydrous

(iii) removal of any other substituent protecting groups R9.

Compounds of formulas (IIa) and (IIb) as defined above are important precursors useful for the preparation of imaging agents in vivo and thus form other aspects of the invention.

Preferred precursors of formulas (IIa) and (IIb) include those wherein R2 is hydrogen or C1-6 alkyl, suitably methyl, more suitably R2 is hydrogen; R1 is C1-6alkyl, suitably methyl; These precursors in which R3 is nitro may have particular utility. Compounds of formula (IIa) and (IIb) wherein R 9 is hydroxyl or C 1-6 alkoxy or a protected derivative thereof may also have particular utility. Such a preferred precursor is 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole.

Conveniently, a precursor of formula (III), (Ha), or (IIb) could be provided as part of a kit, for example for use in a radiopharmacy. The kit may contain a cartridge that can be plugged into a properly adapted auto synthesizer. The cartridge may contain, apart from the precursor, a column for removing unwanted fluoride ion, and an appropriate vessel connected to allow the reaction mixture to be evaporated and to allow the product to be formulated as required. The reagents and solvents and other consumables required for synthesis can also be included together with a compact disc carrying computer program that allows the synthesizer to be operated in a mode to meet customer requirements for radioactive concentration, volumes, release etc. Conveniently, all kit components are disposable to minimize the possibility of contamination between runs and can be sterile and of assured quality.

The invention further provides a radiopharmaceutical kit for the preparation of an 18F labeled tracer for use in PET, comprising:

(i) a vessel containing a compound of formula (II), (IIa), or (IIb); and

(ii) means for eluting the vessel with an 18 F source;

(iii) an 18F excess removal ion exchange cartridge; and optionally

(iv) a cartridge for deprotecting the resulting product of formula (I), (Ia), or (Ib).

The invention further provides a cartridge for a radiopharmaceutical kit for the preparation of an 18F labeled tracer for use in PET comprising:

(i) a vessel containing a compound of formula (II), (IIa), or (IIb); and

(ii) means for eluting the vessel with an 18 F source.

Compounds of formula (II), (IIa), and (IIb) may be prepared from commercially available starting materials or using starting materials described in WO 02/16333 and WO2004 / 083195 by standard methods of organic chemistry, for example by methods described below and in the examples.

Compounds of formula (II), (IIa), and (IIb) wherein R 3 is nitro may be prepared by methods analogous to those described in Example 1.

Compounds of formula (II), (Ha), and (IIb) wherein R is chlorine, bromine, iodine, tosylate, or an iodonium salt may be prepared by methods analogous to those described in Schemes 1 to 4 respectively. In Schemes 1 to 6, R is as defined for a compound of formula (I) above. In Scheme 1 is an alkyl or aryl substituent, Ac is acyl, Ts is tosyl, NaHDMS is sodium hexamethyl disilazide, TFA is acidic. trifluoroacetic, Pd 2 dba 3 in Scheme 6 is tris- (dibenzylidene acetone) dipaladium (0) and the other abbreviations are as defined in the Examples. Formula 1 <formula> formula see original document page 17 </formula> Scheme 2

<formula> formula see original document page 18 </formula>

Scheme 3

<formula> formula see original document page 18 </formula> <formula> formula see original document page 19 </formula>

Scheme 5

<formula> formula see original document page 19 </formula>

Compounds of formula (II), (Ha), and (IIb) wherein R 3 is -N 2 + may be prepared from the corresponding compound in which R 3 is nitro by reducing the nitro group to amino, for example using hydrogen and PdJC as catalyst and then diazotation using NaN02-

Compounds of formulas (II), (IIa) s and (IIb) wherein R3 is NR4 (C1-6 alkyl) 2+ may be prepared according to Scheme 6. Scheme 6

<formula> formula see original document page 20 </formula>

The invention is now illustrated by the following Examples, in which the following abbreviations are used: DMF::, Ν-dimethylformamide

DCM: Dichloromethane

EOMCl: ethoxy methyl chloride

DMAP: dimethyl amino pyridine

RT: room temperature

THF: tetrahydro-furan

IMS: industrial methylated volatile hydrocarbons

M.p. : fusion point

eq. : equivalents

EtOAc: ethyl acetate

QMA: Quaternary Ammonium

HPLC: high performance liquid chromatography

ml or ml: milliliter (s)

TLC: thin layer chromatography

v / v: volume / volume

NMR: nuclear magnetic resonance

MS: mass spectrometry Example 1: Synthesis of 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole

<formula> formula see original document page 22 </formula>

Example 1 (i) 4-Acetamido-3-nitro-benzoyl chloride (2) 4-Acetamido-3-nitro-benzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxalyl chloride (4.76 g, 38 mmol), chloroform (50 mL), DMF (few drops) were stirred at 40 ° C for 3 hours. The solvent was removed in vacuo to give a yellow solid which was used in the next step without further purification.

Example 1 (ia), 5-Methoxy-2-amino-benzene thiol (3) 2-Amino-6-methoxy-benzothiazole 10g (55.6 mmol) was suspended in 25% aqueous potassium hydroxide solution and the mixture it was heated under reflux for 24h. The pale yellow solution was cooled and acidified to pH 6 first with 6 N aqueous HCl then with acetic acid. The solid precipitate was filtered, washed with water (3x100 mL), dried (high vacuum) to give the desired material as a pale yellow powder 8.18 g, 95%.

Example KiQ 2- (4-Acetamido-3-nitrophenyl-V6-methoxybenzothiazole (4)

.5-Methoxy-2-amino-benzene thiol 3 (3.88 g, 25 mmol), pyridine (100 mL), and DMAP (few crystals) were stirred at room temperature.

4-Acetamido-3-nitro-benzoyl chloride (25 mmol, as produced above) was added in a portion below 30 ° C. The mixture was stirred for a further 1 hour. The mixture was heated to 80 ° C and stirred over the weekend. The mixture was cooled. The crystals were filtered and washed with IMS to give 2.2g (26% yield) of 2- (4-acetamido-3-nitro-phenyl) -6-methoxy-benzoiazole.

Example 1 (iii) 2- (4-N-Methyl-acetamido-3-nitro-phenyl ') -6-methoxy-benzothiazole (5)

Sodium hydride (6.33 g, 157 mmol) and DMF (400 mL) were stirred at room temperature. 2- (4-Acetamido-3-nitro-phenyl) -6-methoxy-benzothiazole 4 (45 g, 131 mmol) was added in one portion. The mixture was stirred for 1 hour. The mixture was cooled in an ice bath and methyl iodide (23.1 g, 164 mmol) was added in one portion, the temperature remained below 20 ° C.

The mixture was stirred for 3 hours, water (900 mL) was added, the mixture was filtered and washed with water. The solid was recrystallized from IMS to give 43.7g (93% yield) of 2- (4-N-methylacethoxido-3-nitro-phenyl) -6-methoxy-benzothiazole. Mp 168-172 ° C.

Example 1 (iv) 2- (4-Methyl-amino-3-nitro-phenyl) -6-hydroxy-benzothiazole (6)

A mixture of 2- (4-N-methyl-acetamido-3-nitro-phenyl) -6-methoxy-benzothiazole (58 g, 162 mmol), hydrobromic acid (500mL, 48% aqueous solution) and hydrobromic acid (500mL, 45% in acetic acid) was stirred at 135 ° C for 5hr. The mixture was cooled to room temperature and the solid was filtered off and washed with a little water. The solid was slurried with water and the pH adjusted to about pH 10 with concentrated ammonia solution. The solid was filtered and washed with water.

The solid was triturated with IMS (200 µl), filtered, and the mixture was boiled with IMS (500 mL) then cooled to room temperature and then filtered. The solid was again boiled with IMS (500 mL) then cooled to room temperature and filtered. The solid was dissolved in hot DMF (200 mL), filtered and water (100 mL) was added. The solid was filtered and washed with IMS. The solid was boiled with water (300 mL) for 5 minutes, cooled, filtered, then washed with water with IMS to give 45.9g (94% yield) of 2- (4-Methyl-amino-3-nitro-phenyl). ) -6-hydroxybenzothiazole. Mp 269-272 ° C.

Example I (V) 2- [3-nitro-4- (methylamino) phenyl] -6-ethoxymethoxy-benzothiazole (7)

A 250 mL 3-neck round-bottom flask was oven dried at 80 ° C overnight. A suspension of 6 (16.6 mmol, 5g) in dry THF (180 mL) has been poured into a 60% NaH dispersion suspension in mineral oil (33.2 mmol, 1.26 g, 2eq). in dry THF (20 mL). Once the addition of pure ethoxy methyl chloride (16.6 mmol, 1.54 mL, leg) was complete and the reaction was stirred overnight. The dark brown mixture was vacuum filtered and the filtrate was concentrated under high vacuum.

The crude product was supported on silica and purified via flash flash chromatography in DCM / EtOAc: 3% EtOAc.

The desired fraction was isolated, concentrated under high vacuum to give 60% of an almost red solid of 95% purity.

Example I (Vi): 2-β-nitro-4- (methyl "formyl-amino) -phenyl]" 6 "ethoxy-methoxy-benzothiazole (8)

All glassware was oven dried at 80 ° C overnight.

In a three-neck IL round bottom flask equipped with a condenser and thermometer, acetic anhydride (15mL, 160 mmol, 22eq) was added dropwise in a solution of formic acid (160 mmol, 6mL, 22eq) at 0 ° C. The mixture was stirred for 15 minutes at 60 ° C.

A solution of 7 (7.2 mmol, 2.6g) in dry DCM (310 mL) is added dropwise at 0 ° C in the mixed anhydride. Stirring was continued at this temperature for one hour and the light orange solution was stirred 5 days at 40 ° C.

The reaction was followed by HPLC: after 5 days 60% conversion to the desired product was observed.

HPLC Conditions:

Phenomenex Luna Speaker 150 mm χ 4.6 mn

Flow 1 mL / min

Solvent: Acetonitrile (B) and Water (A)

Detection: 254-214

Gradient 5-95% B over 8 minutes

Retention Time: 9.5 minutes

The light orange solution was washed with 1 N aq NaOH (3x100 mL), water (3x100 mL), dried over magnesium sulfate and concentrated under high vacuum.

The bright orange crude product was supported on silica and purified via flash flash chromatography in 3-10% DCM / EtOAc: EtOAc.

The desired fraction was isolated, concentrated under high vacuum to give 54.2% of an almost yellow solid of 98% purity.

Example 1 (vii) Preparation of 2- [3- [18F] fluoro-4- (methylamino) phenyl] -6-hydroxybenzothiazole (11) - see Scheme below (Approach 1)

<formula> formula see original document page 26 </formula>

[18F] fluoride (in 200 μΐ, 95% water-18O enriched), Kryptofix 2.2.2 .2.5 mg (in 0.5 mL acetonitrile) and 50 μΐ, 0.1M K2CO3 were added in a pot of glassy carbon reaction. The solution was then evaporated to dryness using a stream of nitrogen and warming the reaction vessel at 5 minutes and 10 minutes respectively to aid azeotropic drying. The reaction vessel was cooled to room temperature and 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole (8) (5.0 mg) in 1 mL of anhydrous dimethyl sulfoxide was added. The reaction vessel was sealed and heated for 10 minutes at 130 ° C. The crude mixture was analyzed by HPLC and TLC.

0.25mL 6 M HCl and 0.5mL DMSO were added to the crude reaction solution of 2- [3- [18F] fluoro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy- benzothiazole (9) and heated to 125 ° C for 10 minutes. The reaction was then cooled to room temperature and neutralized using 2 M sodium acetate resulting in the synthesis of 2- [3- [18F] fluoro-4- (methylamino) phenyl] -6-hydroxybenzothiazole (11) . The crude mixture was analyzed by HPLC and TLC.

HPLC purification and formulation

.2- [3- [F] fluoro-4- (methylamino) phenyl] -6-hydroxybenzothiazole (11) was purified by HPLC using a Phenomenex Prodigy ODS5IO preparative column μιη χ 250 mm χ 10 mm (part OOG-4088-NO) (the column is eluted with acetonitrile / 40/60 pH 7 (v / v) triethylamine phosphate buffered solution). The control method is 0-15 minutes 5 mL / minute, 15.5-39.9 minutes 8 mL / minute, 40 minutes 5 mL / minute. The product elutes with a reaction time of 22-23 minutes (in a volume of 8 mL).

The HPLC purified "cut" was diluted to 50 mL with the addition of distilled water. The product was then "trapped" in a C8-Sep-Pak cartridge and then eluted from the cartridge with 1 mL of ethanol. Ethanol was then removed under vacuum and the final product was formulated in 10% ethanol / 90% phosphate buffered saline.

Example 2 Preparation of 2-Γ3-Γ F1fluoro-4- (methylamino) phenyl "i-6-hydroxybenzothiazole (11) - vein Scheme above (" Approach 2)

Example 2 (i) Preparation of | "K / K2.2.2] + 18F" (using 95% water enriched with 18O).

After irradiation, the target content was passed through a QMA resin filled column. The column was purged with helium for 5 minutes. The fluoride [18F] adsorbed onto the resin was eluted into a reaction flask containing 4 mL of a 96: 4 acetonitrile-water mixture (by volume) containing 19.1 mg Kryptofix 2.2.2 and 2.9 mg of K 2 CO 3; The solution was then evaporated and coevaporated with anhydrous acetonitrile (2 x 1 mL) to dryness in a stream of nitrogen at 110 ° C.

Example 2 (ii) Preparation of 2- [3- [F] fluoro-4- (methyl-formyl-amino) -phenyl-6-ethoxy-methoxy-benzothiazole (9) and 2- [3- [18-fluoro-4- (methylamino) phenyl] -6-ethoxy-methoxy-benzothiazole (10).

A solution of 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole (8) (3.0 mg) in anhydrous acetonitrile (0.1 mL) was added. in a solution of [K / K2.2.2] F "in anhydrous acetonitrile (0.25 mL). The reaction mixture was heated at 150 ° C for 15 minutes. The crude mixture was analyzed by analytical HPLC. Example 2 (iii) Conversion of 2-Γ3-Γ Flfluoro-4- (methyl-formylamino) -phenyl] -6-ethoxy-methoxy-benzothiazole (9) to 2-r3-r18Flfluoro-4- (methyl-amino) -phenyl1-6 -ethoxy-methoxy-benzothiazole (10).

About 0.2 mL of the above reaction mixture was added in a solution of NaH (3.2 mg) in anhydrous acetonitrile (0.2 mL) at room temperature. The resulting mixture was heated at 100 ° C for 5 minutes. The crude mixture was analyzed by analytical HPLC.

Preparation of 2-β-Fluoro-4- (methyl-aminoyphenyl] -6-hydroxy-benzothiazole (11).

A solution of concentrated HCl in MeOH (1: 2) (0.25 mL) was added dropwise to the above reaction mixture and heated at 100 ° C for .5 minutes. The crude mixture was analyzed by analytical HPLC.

Example 3: Comparative, fluorination | 18Fl from different precursors.

Radiofluorination of various benzothiazole precursor compounds using methods analogous to those described in Example 1 (vii) gave the results shown in Table 1. Crude yield was calculated from HPLC-measured radiochemical purity, corrected for product loss by HPLC and vessel retention reaction

<formula> formula see original document page 28 </formula>

<table> table see original document page 28 </column> </row> <table>

Example 4: Automatic Synthesis of 2- [3- [18F1fluoro-4- (methylamino] phenyl-6-hydroxybenzothiazole (11)

Reagent positions in a TRACERlab FXFn Automatic Synthesizer Unit (GE Healthcare Ltd) were loaded with the following solutions:

i. Potassium carbonate O5I M in water (0.5 mL)

ii. Kryptofix 2.2.2 0.13M in acetonitrile (0.5 mL)

iii. Precursor solution: 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole (8) 0.1 M in DMSO (1.0 mL)

iv. 4 M hydrochloric acid (0.25 mL)

v. Ethanol (1.0 mL)

saw. 0.01 M phosphate buffer, pH 7.4 (13.1 mL)

ι δ ·

When a solution of fluororetof F] in enriched water1 $

with [O] (121 MBq) had been loaded at the synthesizer start position the operator started the program causing the following sequence of events to occur.

The fluoride solution passed through a QMA cartridge (preconditioned with 10 mL 0.5 M aqueous potassium carbonate and 20 mL water) trapping the fluoride and sending the enriched water for disposal. The QMA cartridge was then eluted with 0.1 M potassium carbonate solution to recover the fluoride and the eluent was directed to the reactor vessel. Kryptofix 2.2.2 solution was added to the reactor and the mixture was heated at 60 ° C for 5 minutes under a gentle flow of nitrogen under reduced pressure. The temperature was then raised to 120 ° C and held under vacuum for 7 minutes to dry the reactor contents. After cooling to 50 ° C, the Precursor solution was added to the reactor and the temperature was raised to 135 ° C for 10 minutes. This step allows fluoride [18F] to be incorporated into the organic molecule. The solution was cooled to 50 ° C and 4 M hydrochloric acid was added. The mixture was heated to 125 ° C for 5 minutes to cause deprotection of the intermediate compound and, after cooling to .40 ° C, the crude product solution was injected into a Phenomenex Gemini C18 HPLC column (250 mm χ 21.2 mm, 5μηι). The column was eluted with 6 mM hydrochloric acid-acetonitrile (53:47, v: v) mixture at 10 mL / min. The desired product was identified by radio detection and collected by cutting. The obtained solution was diluted with water (150 mL) and passed through Sep-Pak® Plus C8 cartridge (preconditioned with 10 mL ethanol and 10 mL water) so that the product was retained in the cartridge. The cartridge was eluted with ethanol into the product bottle containing propylene glycol (0.9 mL). Phosphate buffer was also passed through the cartridge into the product vial to give the formulated product. Product yield was 10.8% (uncorrected, based on initial activity of [18F]) and radiochemical purity was> 99%.

Example 5: Alternative Synthesis of 2-β-nitro-4- (methyl-formyl-amino-phenyl-ethoxy-methoxy-benzothiazole (8)

Example 5 (i): Synthesis of 4-Chloro-N- (4-hydroxy-phenyl) -3-nitrO "

benzamide

It is dissolved under an inert atmosphere with stirring in dry DMF (50 mL) and cooled in an ice bath. Triethylamine (TEA, 11 g, 0.11 mol) was added and stirring continued for 1 hour. 4-Chloro-3-nitro-benzoyl chloride (22.2 g 0.1 mol, Acros and Aldrich) was added slowly and stirred overnight. The precipitated triethylamine hydrochloride salt was filtered off and DMF was removed under reduced pressure. The residue was extracted with EtOAc (3 x 100 mL) and citric acid (1 M, 3 x 100 mL). The organic phase was dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The title product was recrystallized from methanol / water (1: 1, 250 mL), 85% yield, and analyzed by NMR and MS.

The

.4-Amino-phenol (12 g, 0.11 mol, Acros and Aldrich) was Example 5 (ii): Synthesis of 4-Chloro-N- (4-ethoxy-methoxy-phenyl) -3-nitro-benzamide

<formula> formula see original document page 31 </formula>

.4-Chloro-N- (4-hydroxy-phenyl) -3-nitro-benzamide (14.6 g, 0.05 mol) was added to an oven dried and blasted 2-neck round-bottom flask. with N2. Sufficient dimethoxyethane (DME, 100 mL) was added to dissolve the amide. The mixture was cooled in an ice bath and sodium hydride (NaH, 50% in oil, 3.6 g total, 0.075 mol) was added in small portions with vigorous stirring. One hour after completion of the addition, chloro methoxyethane (7.13 g, 0.075 mol, commercially available) was added dropwise via an equalized pressure dropping funnel. The reaction was followed by TLC (dichloromethane, DCM, methanol, MeOH, 95: 5). The reaction mixture was poured into ice water and extracted with EtOAc (3 x 50 mL). The organic phase was dried (MgSO 4) and evaporated under reduced pressure. The crude product was recrystallized from hexane / ethyl acetate 1: 4. to give 81% of title compound.

Example 5 (iii): Synthesis of 4-Chloro-N- (4-ethoxy-methoxy-phenyl) -3-nitro-thio-benzamide

<formula> formula see original document page 31 </formula>

.4-Chloro-N- (4-ethoxy-methoxy-phenyl) -3-nitro-benzamide (3.5 g, 10 mmol), P4S10 phosphorus pentasulfide (0.81 g, 1.83 mmol, commercially available) , hexamethyl disiloxane (2.7 g, 16.7 mmol, commercially available) and toluene (10 mL) were added in a 100 mL round bottom flask and blasted with nitrogen. The mixture was heated under reflux and was followed by TLC. Heating continued until no more initial benzamide remained. Microwave heating can also be used. The reaction mixture was cooled to room temperature. Potassium carbonate solution (4 mL of 5.3 M solution) was added. Acetone (10 mL) was added and the mixture was stirred for 1 hour in an ice bath, and extracted with toluene and water. The organic phase was dried (MgSO 4) and toluene was removed under reduced pressure and the residue was purified by flash chromatography with ethyl acetate / hexane as eluent.

Example 5 (iiia) Alternative Thioamidation Procedure: Synthesis of N- (4-benzyloxy-phenyl) -4-chloro-3-nitro-thio-benzamide

N- (4-Benzyloxy-phenyl) -4-chloro-3-nitro-benzamide (19.15 g, 50 mmol), Lawesson's reagent (11 g, 27 mmol, commercially available) and dioxane (150 mL) were stirred together under reflux for 4 h. When no more initial amide was present, as shown by TLC, the reaction mixture was cooled and the solvent removed under reduced pressure. The crude product was dissolved in minimal boiling toluene for recrystallization. The purified product was filtered and washed with cold toluene and cold hexane to give thioamide in 77% yield.

Example5Civa): Synthesis of 6-benzyloxy-2- (4-chloro-3-nitro-phenyl) -benzothiazole

Triton B:

N- (4-Benzyloxy-phenyl) -4-chloro-3-nitro-benzobamide (2 g, 5 mmol) was dissolved in methanol (100 mL). Sodium hydroxide (1.6 g in 5 mL water) was added followed by Triton B (2.1 mL, 5 mmol, commercially available). The mixture was cooled in an ice bath. Potassium ferri (III) cyanide (13.2 g in 50 mL water) was added dropwise with vigorous stirring. The reaction mixture was allowed to warm overnight and was further heated at 130 ° C for 1 hour. The reaction mixture was cooled and extracted with ethyl acetate / water. The organic phase was dried and the solvent removed under reduced pressure. The product compound was purified by flash flash chromatography with hexane / ethyl acetate as eluent.

Example 5 (iv): Synthesis of 6-Ethoxy-Methoxy-2- (4-chloro-3-nitro-phenyl) -benzothiazole

Using methods analogous to those described in Example 5 (iva), the thio-benzamide prepared in Example 5 (iii) may be cyclized to form the title compound.

Example 5 (v): Synthesis of 6-benzyloxy-2- (4-methyl-amino-3-nitro-phenyl) -benzothiazole and 6-ethoxy-methoxy-2-4-methyl-amino-3-nitro- phenyl) benzothiazole (7)

The compounds of Examples 5 (iva) and 5 (iv) respectively, are reacted with methylamine in aqueous solution, heating to 130 ° C for example in a microwave oven. The reaction mixture is extracted with ethyl acetate / water and the organic phase is dried, before removing the solvent under reduced pressure. The title products are purified by flash chromatography using hexane / ethyl acetate.

Example 5 (vi): Synthesis of 2-3-nitro-4- (methyl-formyl-amino) -phenyl-6-benzyl-oxy-benzothiazole and 2- [3-nitro-4-methyl-formyl-amino) -amide phenyl-6-ethoxy-methoxy-benzothiazole (8)

The title compounds are prepared from the compounds of Example 5 (v) respectively using formylation methods analogous to those described in Example 1 (vi). Example 6: Alternative Synthesis of 2 - ["3-nitro-4- (methyl-formyl-amino) -phenyl-6-ethoxy-methoxy-benzothiazole (8)

The synthesis is carried out, analogously to Example 5, but starting with 4-amino-3-chloro-phenol to prepare 6-ethoxy-methoxy-2- (4-chloro-3-nitro-phenyl) -benzothiazole via 4-chloro-N- (4-hydroxy-2-chloro-phenyl) -3-nitro-benzamide, 4-chloro-N- (4-ethoxy-methoxy-2-chloro-phenyl) -3-nitro-benzamide, and 4-chloro-N - (4-ethoxy-methoxy-2-chloro-phenyl) -3-nitro-benzobamide. Cyclization of 4-chloro-N- (4-ethoxy-methoxy-2-chloro-phenyl) -3-nitro-thio-benzamide to form 6-ethoxy-methoxy-2- (4-chloro-3-nitro-phenyl) -benzothiazole is performed using literature methods, for example Bowman et al. Tetrahedron, 47 (48), 10119-10128 (1991); Couture and Glandclaudon, Heterocycles, 22 (6) 1984; Hutchinson et al., Tetrahedron Lett 2000, 41 (3), 425-8. Subsequent methylation and formylation are then performed as described in Example 5.

Claims (17)

Process for preparing a compound of formula (I): in which phenyl ring A is optionally substituted with 1 to 4 substituents; R 1 is selected from C 1-4 alkyl C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl; characterized in that it comprises: (i) reaction of a corresponding compound of formula (II): wherein ring A is optionally substituted as defined for the compound of formula (I) ; R is selected from hydrogen, C1-6 alkyl, C1-10 alkyl, C6-4 aryl, C6-6 alkyl, - (CH2 CH2 O) q -CH3 wherein q is an integer from 1 to 10; R1 is as defined for the compound of formula (I); and R3 is a leaving group; with fluoride to give a compound of formula (III) <formula> formula see original document page 35 </formula> ('") .12 · wherein ReR are as defined for the compound of formula (I) and phenyl ring A is substituted as defined for the compound of formula (I), followed by step (ii) and optionally step (iii) in any order λ (ii) conversion of -C (O) R group to hydrogen, suitably by hydrolysis (iii) removal any other protecting groups. Process according to claim 1, characterized in that the phenyl ring A is optionally substituted with 1 to 4 organic substituents selected from fluoro, chloro, bromo, iodo, cyano, nitro, -R, -OR, -OC (O) Rs -C (O) R, -SR, -NR 2, -C (O) NR 2 wherein R at each occurrence is selected from C 1-6 alkyl, C 2-4 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyC 1-6 alkyl, C 1-6 haloalkyl, C 2-6 halo alkenyl, C 2-6 halo alkynyl, C 1-6 haloalkoxyC 1-6 alkyl, C 5 -naryl, C 5-2 hetaryl in which said aryl and hetaryl substituents may be further substituted with the non-aryl and non-aryl substituents. hetaryl listed for phenyl ring A, and a protected derivative of any of them. A process for preparing a compound of formula (Ia): wherein R 1 is selected from C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl; R7, R8, R9, and R10 are each independently selected from hydrogen, fluoro, chloro, bromo, iodo, C1-4 alkyl, C2-4 alkenyl, C2-6 alkynyl, (CH2) mOR11 (where m = 1, 2, or 3) , CF 3, CH 2 -CH 2 Y, O-CH 2 -CH 2 Y, CH 2 -CH 2 -CH 2 Y, O-CH 2 -CH 2 -CH 2 Y (wherein Y is selected from fluoro, chloro, bromo, and iodo), CN, (C = O) -R11, N (R11) 2, NO2, (C = O) N (Ru) 2, O (CO) R11, OR11, SR11, COOR11, Rph, CR11 = CR11-Rph, CR112-CR1 ^ -Rph (in the wherein Rph represents a phenyl group substituted or unsubstituted with phenyl substituents being selected from any of the non-phenyl substituents defined for R7 to R10 and wherein R11 is H or C1-4 alkyl) and a protected derivative of either; and phenyl ring A is substituted with 1 to 3 substituents being selected from any of the non-phenyl substituents defined for R to R 10: characterized in that it comprises: (i) reaction of a corresponding compound of formula (IIa): <formula> wherein R1 is defined for the compound of formula (Ia), phenyl ring A is substituted as defined for the compound of formula (Ia); and R is selected from hydrogen, C1-10 alkyl, C1-10 haloalkyl, C6-4 aryl, Co-arylalkyl, - (CH2 CH2 O) q -CH3 where q is an integer from Ia 10; R3 is a leaving group; R7, R8, R95 and R10 are as defined for the compound of formula (Ia); with fluoride to give a compound of formula (IIIa) wherein ReR are as defined for the compound of formula (Ha), phenyl ring A is substituted as defined for the compound of formula (Ia); R 7, R 8, R 9, and R 10 are as defined for the compound of formula (Ia); followed by step (ii) and optionally step (iii) in any order (ii) conversion of -C (O) R group to hydrogen, suitably by hydrolysis (iii) removal of any other protecting groups. A process for preparing a compound of formula (Ib): wherein R 1 is selected from C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl; R9 is selected from hydroxyl, -NO2, -CN5 -COOR, -OCH2OR, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, halo, and a protected derivative of either, and is preferably selected from hydroxyl, C1-6. alkoxy, and a protected derivative of any of them, and is more preferably selected from hydroxyl, methoxy, and a protected derivative of either; characterized in that it comprises: (i) reaction of a corresponding compound of formula (IIb): wherein R1 is selected from C1-4 alkyl, C2-4 alkenyl, and C2. 6 is alkynyl, and R is selected from hydrogen, C 1-10alkyl, C 1-10 alkyl, C 6-14 aryl, C 6 -aryl alkyl, - (CH 2 CH 2 O) q -CH 3 wherein q is an integer from 1 to 10; R3 is a leaving group; R 9 is as defined for the compound of formula (Ib); with fluoride to give a compound of formula (IIIb) wherein ReR are as defined for the compound of formula (IIb); R 9 is as defined for the compound of formula (Ib); followed by step (ii) and optionally step (iii) in any order (ii) conversion of -C (O) R2 group to hydrogen, suitably by hydrolysis (iii) removal of any other substituent protecting groups R9. Process according to any one of claims 1 to 4, characterized in that the fluoro group in the compound of formula (I), (Ia), or (Ib) is fluoro [18F] and the fluoride used in step ( i) of the process is fluoride [18F]. Process according to any one of claims 1 to 5, characterized in that R in the compound of formula (II), (IIa) or (IIb) is selected from: nitro, -N2 +, chlorine, bromine, iodine, NR4 (C1-6alkyl) 2+ wherein R4 is C1-6 alkyl or a group of formula (X): <formula> formula see original document page 39 </formula> (X) -OSO2R5 wherein R5 is selected from C1-6alkyl; C1-6 -haloalkyl such as C1-6perfluoroalkyl, aryl such as phenyl or tolyl (e.g. para-tolyl), and a group of formula (X) as defined above; and in which R 6 is selected from hydrogen, C 1-6 alkyl, halo, nitro, and a group of formula (X) as defined above. Process according to claim 6, characterized in that R 3 is selected from: nitro, -N 2 +, chloro, bromo, iodo, -NR 4 (C 1-6 alkyl) 2+ wherein R 4 is C 1-6 alkyl; -OSO 2 R 5 wherein R 5 is selected from C 1-6 C 1-6 alkyl-alkyl such as C 1-6 perfluoroalkyl, aryl such as phenyl or tolyl (e.g. para-tolyl); and in which R 6 is selected from hydrogen, C 1-6 alkyl halo, and nitro. Process according to Claim 6 or 7, characterized in that R is nitro. Process according to any one of claims 1 to 8, characterized in that R 1 is C 1-6 alkyl, and particularly methyl. Process according to any one of claims 1 to 9, characterized in that R in the compound of formula (II), (Ha), or (IIb) is selected from hydrogen and C1-4 alkyl and is more preferably hydrogen. Process according to any one of claims 1 to 9, characterized in that step (ii) is carried out by reaction with a non-nucleophilic base such as sodium hydride in an aprotic solvent such as acetonitrile or propionitrile and in elevated temperature such as 40 ° C to 120 ° C, typically around 100 ° C. Compound, characterized in that it is of formula (IIa) or (IIb) as defined in any one of claims 3 to 10. 13. A compound, characterized in that it is of formula (IIb): <formula> formula see original document page 41 </formula> which: R2 is hydrogen or C1-6alkyl (suitably methyl); R1 is C1-6alkyl (suitably methyl); R3 is selected from nitro, -NN2, chlorine, bromine, iodine, -NR4 (C1-6alkyl) 2+ wherein R4 is C1-6alkyl; -OSO 2 R 5 wherein R 5 is selected from C 1-6 alkyl, C 1-6 haloalkyl such as C 1-6perfluoroalkyl, aryl such as phenyl or tolyl (e.g. para-tolyl); and wherein R 6 is selected from hydrogen, C 1-6 alkyl, halo, and nitro; and <formula> formula see original document page 41 </formula> R9 is hydroxyl or C1-6alkoxy or a protected derivative thereof. Compound of formula (IIb) according to claim 12 or 13, characterized in that R is hydrogen, and R is nitro. 15. A compound characterized in that it is 2- [3-nitro-4- (methyl-formyl-amino) -phenyl] -6-ethoxy-methoxy-benzothiazole. Radiopharmaceutical kit for the preparation of an 18F labeled tracer for use in PET, comprising: (i) a vessel containing a compound of formula (II), (Ha), or (IIb) as defined in any of one of claims 12 to 15; and (ii) means for eluting the vessel with an 18 F source; (iii) an 18 F "excess removal ion exchange cartridge; and optionally (iv) a resulting product deprotection cartridge of formula (I), (Ia), or (Ib) as defined in any one of claims 1 to 5. Cartridge for a radiopharmaceutical kit for the preparation of an 18F labeled tracer for use in PETj comprising: (i) a vessel containing a compound of formula (II), (Ha), or (IIb) as defined any one of claims 12 to 15; and (ii) means for eluting the vessel with an 18 F source.